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One-year tolerability and efficacy of sumatriptan nasal spray in adolescents with migraine: results of a multicenter, open-label study
CLINICAL
THERAPEUTICSVVOL.
22, NO. 12,200O
One-Year Tolerability and Efficacy of Sumatriptan Spray in Adolescents with Migraine: Results of a Multicenter, Open-Label Study
Nasal
A. David Rothner, MD,’ Paul Winner, DO,2 Robert Nett, MD,3 Mahnaz Asgharneja f, PharmD,4 Antonio Luurenza, MD,4 Randall Austin, MA, and Margaret Peykamiun4 ‘The Cleveland Clinic, Cleveland, Ohio, 2Pafm Beach Headache Centel; West Palm Beach, Florida, 3San Antonio Center for Clinical Research, San Antonio, Texas, and 4Glaxo Wellcome Inc, Research Triangle Park, North Carolina
ABSTRACT Objective: The objective of this study was to determine the l-year tolerability and efficacy of sumatriptan nasal spray (NS) at doses of 5, 10, and 20 mg for the treatment of acute migraine in adolescents. Methods: This was a prospective, multicenter, open-label, 1-year, multiple-attack study. Adolescents (aged 12-17 years) with a >6-month history of migraine with or without aura, 2 to 8 moderate or severe migraines per month, and a typical migraine duration of ~4 hours were eligible for participation. After initial treatment with sumatriptan 10 mg, the dose could be adjusted down to 5 mg or up to 20 mg at the investigator’s discretion to optimize tolerability or efficacy. Patients could treat an unlimited number of moderate or severe migraine attacks, provided there was a 24-hour headache-free period between treated attacks and a 2-hour period between doses of sumatriptan NS. A second dose of sumatriptan NS was available for headache recurrence 2 to 24 hours after initial treatment; no more than 2 doses could be used within a 24-hour period. Adverse events, vital signs, electrocardiographic and physical findings, and laboratory variables were assessed. Headache response (reduction of moderate/severe predose pain to mild/no pain) and painfree response (reduction of moderate/severe predose pain to no pain) were reported by patients 2 hours after dosing. Portions of this study were presented at the American 2000, Montreal, Quebec, Canada. Accepted for publication
November
Printed in the USA. Reproduction
0149.2918/00/$19.00
Headache
Society Annual Scientific Meeting, June 22-26,
7, 2000. in whole or part is not permitted.
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Results: A total of 437 patients treated 21 migraine; 3272 total attacks were treated, with 3675 drug exposures (mean. 1.1 dose/attack). Patients had a mean age of 14.1 years, 91% were white, and 53% were female. Seven patients used the 5-m:: dose; meaningful conclusions concerning this dose could not be made. Drug-related adverse events were reported in 33% of attacks with the IO-mg dose and 31% with the 20-mg dose; most were related to taste disturbance. Adverse events did not increase with a second dose or over time. Four percent (16/437) of patients withdrew due to drug-related adverse events. One serious adverse event, a facial-nerve ischemic event (IO-mg dose), was considered drug related. No drugrelated changes in vital signs or electrocardiographic findings were observed. Headache response 2 hours after dosing was reported by 76% of patients taking the IO-mg dose and 72% of those taking the 20-mg dose. Pain-free response 2 hours after dosing was reported by 43% and 40% of patients in the IO- and 20-mg groups, respectively. Cordusions: Based on these results, sumatriptan NS at doses of 10 and 20 mg was well tolerated and effective in the l-year treatment of multiple migraine attacks in adolescents. Key words: migraine, adolescent, sumatriptan, tolerability, multiple attacks. (Cl&r Thet: 2000;22: 1533-I 546)
INTRODUCTION Migraine is a common, episodic neurologic disorder with a worldwide prevalence of 8% to 20% in adults and 4% to 10% in adolescents.’ The onset of migraine often occurs in childhood. and many patients experience their first episode by the end of
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adolescence.’ Migraine occurs in equal proportions of males and females before puberty but occurs predominantly in females (3:l) after menarche.’ The clinical presentation of migraine in adolescents is similar to that in adults; however, adolescents experience a higher incidence of associated symptoms and pulsating bilateral pain. and a shorter duration of attacks compared with adults.3.” In general. migraine therapy in adolescents has focused on avoidance of trigger factors. adequate sleep, and limited treatment with nonsteroidal anti-inllammatory medications.5-x Sumatriptan nasal spray (NS) has been proved effective in adults who experience a rapid onset of migraine pain and associated symptoms.” -I ’ Results of a recent study of sumatriptan NS 20 mg” indicated that its pharmacokinetic parameters are similar in adolescents and adults. and suggested that dosing used in adolescents should be similar to that used in adults. In addition, a single-attack. placebo-controlled study in adolescents’? indicated that sumatriptan NS was effective and well tolerated. with the 20-mg dose having the best overall efficacy and tolerability. In that study, headache response was greater with sumatriptan NS 10 and 20 mg compared with placebo as early as 1 hour after dosing (56% and 56% vs 41 c/c. respectively: P < 0.05). Furthermore, pain-free response 2 hours after dosing was greater with sumatriptan NS 20 mg compared with placebo (36% vs 25%, respectively: P < O.OS), and photophobia and phonophobia were significantly reduced compared with placebo (36% vs 48% and 23% vs 44%. respectively: P < 0.05). Taste disturbance was the most commonly reported adverse event (AE), and no drug-related serious AEs or clinically relevant changes in lab-
A.D. ROTHNER
ET AL.
oratory variables, electrocardiographic findings, or vital signs were reported. Currently, no formulation of sumatriptan has been approved for use in adolescents. Although the results of the single-attack, placebo-controlled study I3 are encouraging, further investigation into the long-term tolerability of sumatriptan NS over multiple attacks is needed in this population. We report the results of a large-scale, multipleattack, open-label study of the unrestricted use of sumatriptan NS 5, 10, and 20 mg to assess its long-term (1 year) tolerability and efficacy in the treatment of acute migraine in adolescents.
Females were excluded if they were pregnant or breast-feeding, or were sexually active without using adequate contraception. Patients could not use ergotaminecontaining drugs or derivatives or any other 5-HT,-agonist within 24 hours before or after treatment with study medication. Monoamine oxidase inhibitors could not be used for ~2 weeks before screening and throughout the course of the study. Selective serotonin reuptake inhibitors could not be used from screening through study exit. With the exception of these 2 types of agents, patients were allowed to continue prophylactic migraine medication.
PATIENTS AND METHODS
Study Procedures
Inclusion and Exclusion
Criteria
Males and females, aged 12 to 17 years, with a diagnosis of migraine with or without aura based on International Headache Society criteria (categories 1.1 and 1.2)t4 and having a 26-month history of moderate or severe attacks were eligible for study participation. Patients were required to have a history of 2 to 8 moderate or severe migraine attacks per month for each of the 2 months preceding study enrollment and a typical migraine duration of ~4 hours. Patients were also required to have ~15 days of tension headache per month and to have failed to achieve relief with 21 over-the-counter or prescription migraine medication. Patients were excluded from the study if they had a history of congenital heart disease, cardiovascular disease, Prinzmetal’s angina, atherosclerotic disease or cerebrovascular pathologic conditions including stroke, any other clinically significant medical condition, or evidence of alcohol, drug, or substance abuse within the previous year.
Forty-six sites in the United States received institutional review board approval to enroll patients. Patients and their parents or legal guardians provided written informed consent before study enrollment. Patients were screened in a migrainefree state. At screening, demographic information and medical and migraine histories were obtained, and complete physical and neurologic examinations were conducted, including vital signs, clinical laboratory testing (hematology, blood chemistry, and urinalysis), serum pregnancy testing (females), and 12-lead electrocardiography (ECG). Patients who met the inclusion criteria received instruction in the study procedures and use of the NS device and patient diary. Patients could treat an unlimited number of moderate or severe migraine attacks with sumatriptan NS, provided a 24hour headache-free period was maintained between treated attacks and a 2-hour period was maintained between doses. A second dose of sumatriptan NS was available for the treatment of headache recur-
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rence 2 to 24 hours after initial treatment; no more than 2 doses of sumatriptan NS could be used within any 24-hour period (maximum, 40 mg). After initial treatment with sumatriptan 10 mg, dosage adjustment down to 5 mg or up to 20 mg could be made at the investigator’s discretion to optimize tolerability or efficacy. No patient was allowed to use >l dose level of sumatriptan NS at a single time. Patients were required to treat their migraines at home in the presence of a parent or guardian and to record the date, time, and pain intensity of each attack, as well as the time study drug was taken. Patients were instructed to contact study personnel by telephone after treatment of the first migraine. Patients returned to the clinic at 3-month intervals and at study exit (I year after enrollment); at these visits, physical and neurologic examinations and assessment of vital signs were conducted, medical and migraine histories were updated, and pregnancy tests were performed. An independent cardiologist with experience in adolescent cardiology assessed baseline, exit, or unscheduled ECGs when this was clinically indicated or required by the protocol. Study personnel contacted patients approximately every 6 weeks to determine compliance with enrollment criteria, particularly with respect to pregnancy, use of concomitant medications, and dosing procedures. Patients who had not treated a migraine within 3 months were asked to return to the clinic for retraining and reevaluation of eligibility.
End Points The primary study end point was the occurrence and severity of AEs at each dose of sumatriptan NS. Secondary end
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points included headache response and pain-free response 2 hours after dosing, headache recurrence, use of rescue medication, proportion of patients whose sumatriptan dose was adjusted, and nunIber of NS devices used per attack at each dose.
Tolerability Assessment Tolerability assessments included the incidence and severity ofAEs (mild, moderate, or severe), as well as the occurrence of abnormalities in physical findings, vital signs. clinical laboratory test results, and ECGs. An AE was defined as any untoward medical event occurring after the use of study drug. A serious AE was defined as any medical occurrence that was fatal, life-threatening, or disabling: that required hospitalization; or that caused congenital anomaly in a patient’s offspring. Cancer and overdose of study drug were also considered serious AEs. Study personnel queried patients concerning AEs after treatment of the first migraine, at each study visit, and during routine follow-up telephone calls. Severity ofAEs was assigned by investigators based on their professional judgment.
Efficacy Assessment Patients rated their headache pain before and 2 hours after dosing using a 4-point pain scale (0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain). Headache response was defined as a reduction in predose headache pain severity from moderate or severe to mild or no pain (pain score of 2 or 3 reduced to I or 0). Pain-free response was defined as a reduction from moderate or severe predose pain to no pain (pain score of 2 or 3 reduced to 0).
A.D. ROTHNER
ET AL.
Assessment of Headache Recurrence and Use of Rescue Medication Headache recurrence was defined as a significant worsening of pain (from no or mild pain to moderate or severe pain) 2 to 24 hours after the first dose of sumatriptan in those patients who had reported headache response 2 hours after dosing. Use of rescue medication was defined as use of any medication to treat migraine pain or associated symptoms 2 to 24 hours after taking study drug. Use of a second dose of study drug or rescue medication was recorded in the patient diary. Statistical Analysis All statistical analyses were performed using SAS@ software (SAS Institute, Inc, Cat-y, North Carolina). It was determined that -400 patients were necessary to ensure 300 assessable patients with 26 months of treatment data and 100 patients with 1 year of treatment data. All patients who treated 21 attack with study medication were included in the tolerability population. The intent-to-treat (ITT) population was composed of patients who treated an attack with study medication and returned assessable efficacy data. Last observations were carried forward to account for missing assessments of headache severity. If rescue medication or a second dose of sumatriptan was taken between dosing and the 2-hour assessment, a pain intensity of “severe” was assigned to the 2-hour assessment. Because of the openlabel nonrandomized study design that allowed investigators to adjust the dose based on individual patients’ needs, inferences drawn from statistical comparisons of tolerability and efficacy between treatment groups would not have been valid.
Therefore, descriptive statistics are reported. A per-protocol analysis was not performed. The tolerability analyses included extentof-exposure and AE profiles. Extent of exposure included the total number of treated attacks, the actual number of doses taken, and the mean number of doses per patient and per attack. AEs were translated into preferred terms, then sorted into group terms. The overall frequency of patients reporting AEs was tabulated for each dose of sumatriptan. Separate tabulations were made by numbers of patients for drug-related AEs, event intensity, and serious AEs. Abnormalities in clinical laboratory test results, vital signs, ECG data, and physical findings were summarized over the l-year study. The efftcacy analyses summarized headache and demographic characteristics, headache response, pain-free response, and headache recurrence at baseline and 2 hours after dosing by dose and number of attacks using descriptive statistics (frequency counts, percentages, means, SDS, and ranges, as applicable). Values were generated for the l-year (overall) and 6month time points. The mean number of NS devices used per attack was calculated for each sumatriptan dose.
RESULTS Patients Of the 518 patients enrolled in the study, 437 patients treated 21 migraine with sumatriptan NS (tolerability population). Twelve patients in the tolerability population did not return efficacy data; therefore, the ITT population included 425 patients. One hundred eighty-nine (36%) patients completed all 12 months of the
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CLINICAL THERAPEIJTICS”’
study.
most common reasons
presented.
( 152/206; 74%) than were females (I 14/23 I; 49%). Although 60% (260/433) of all patients for whom there was complete information had no prior 5-HT,-agonist exposure, 407~ (I 73/433) had used a sumatriptan formulation before study entry. At baseline, 46% of attacks in the IOmg group and 53% in the 20-mg group were severe in intensity. More than 75% of all patients treated headache pain within 2 hours of its onset (IO-mg group, 75%; 20-mg group, 78%), and mean times to treatment were identical ( I .S hours). Tolerability A total of 3272 attacks were treated in the tolerability population; 3222 attacks were treated in the ITT population. There were a total of 3675 drug exposures: 2374 in the first 6 months of the study and 130 1 in the second 6 months. Overall, the mean
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number of doses used per patient was 8.4 (range, l-54 doses). A mean of 1.1 NS devices was used per attack; this number did not vary by dose. A summary of the overall incidence of AEs by number of patients is presented in Table I. In general. the incidence of AEs was similar between treatment groups. Younger patients reported a higher rate of overall AEs than older patients. However. when taste disturbance was excluded. the incidence of AEs in older and younger patients was similar. AE rates were also similar in males and females receiving sumatriptan 20 mg, although males reported fewer AEs than females in the IOmg group. No differences were observed in the rate of AEs by body weight or dose. The incidence of overall AEs was lowe] in patients in the IO- and 20-mg groups who treated >2 attacks per month compared with those who treated
A.D. ROTHNER ET AL.
Table I. Incidence of overall and drug-related patients and demographic factors.
adverse
events
(AEs),* by number
of
Sumatriptan NS Dose 20 mg
IOmg Total no. of patients’ No. (%) with AEs No. (%) with drug-related AEs Demographic distribution of patients with AEs, no. (%) Age, Y 12-14 15-17 Sex Female Male Body
weight,
433 286 (66) 226 (52)
182/262
(69)
104/171
(61)
164/229
(72)
122/204
(60)
197 126 (64) 88 (45)
83/l 18 (70) 43/79
(54)
66/102 (65) 60/95 (63)
kg
<50 250
93/ 134 (69) 192/298;
(64)
34155 (62) 921142
(65)
NS = nasal spray. ‘AEs were defined as any untoward medical events occurring after the use of study drug. +Although there were 437 patients in the tolerability population, not all patients treated the initial attack with the IO-mg dose, and not all doses were titrated up to the 20-mg dose. *Data were missing for 1 patient.
was similar for the IO-mg (45%) and 20mg (48%) groups per patient, per attack (15%, both 10 and 20 mg), and by age group (48% and 49% in younger patients vs 42% and 47% in older patients, respectively). The percentage of drug-related AEs per patient was slightly higher with the lo-mg dose (52%) than the 20-mg dose (45%) (Table I). Per attack, drug-related AEs occurred in 33% (10 mg) and 31% (20 mg) of all attacks. In the analysis by attack, taste disturbance was also the most commonly reported drug-related AE in the IO-mg (29%) and 20-mg (26%) groups. When taste disturbance was excluded from the tabulations, the incidence of drug-related AEs by attack declined to 7% with both 10 and 20 mg.
Only 1 drug-related serious AE was reported, a facial-nerve ischemic event, which occurred after treatment with sumatriptan 10 mg. The patient was withdrawn from the study; 10 months after the event, the symptoms had resolved, with mild, intermittent sequelae. Few patients (22/437; 5%) discontinued study participation due to AEs; 16 (4%) of these withdrawals were considered drug related: taste disturbance (8 patients), neurologic changes (left hand numbness, 1 patient; facial numbness, 1 patient), migraine and associated symptoms (3 patients), chest pain (2 patients), and abnormal laboratory values ( 1 patient). Two patients had asymptomatic changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values that
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’
Table II. Incidence of overall and drug-related adverse events (AEs), by number of patients (all doses) and number of attacks (all attacks), during the first and second 6-month periods. Sumatriptan NS Dose
AEs by no. (‘5) of patients First 6 months, total patient\ Overall Drug-related Second 6 months, total patients O\ierall Drug-related AEs by no. (%) of attacks First 6 months, total attacks Overall Drug-related Second 6 months, total attacks Overall Drug-related
429 274 (64) 218 (51) I18 64 (54) 44 (37)
IS0 95 (63) 65 (43) 133 73 (551 51 (3X)
147X 620 (42) 542 (37) so0 13s (29) Il.7 (23)
616 240 (39) 190 (31) 654 237 (35) 201 (31)
NS = nasal spray. ‘An AE was defined as any untoward
medical went
occurring
after the use of study drur.
AEs wth taste disturbance BJDrug-related AEs with taste disturbance q Overall AEs without taste disturbance Cl Drug-related AEs without taste disturbance 1 Overall
100 90 80
Sumatriptan NS Dose Figure 1. Incidence of overall adverse events (AEs), drug-related AEs, overall AEs without taste disturbance, and drug-related AEs without taste disturbance, by number of attacks and dose, in a l-year study of sumatriptan nasal spray (NS) in adolescents. An AE was defined as any untoward medical event occurring after the use of study drug.
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A.D. ROTHNER ET AL.
Table III. Adverse events (AEs) occurring at a rate of 23%, by number dose of sumatriptan nasal spray (NS).’ Sumatriptan IOmg Total no. of patients’ No. (%) with AEs Most commonly reported AEs, no. (%) Taste disturbance Ear, nose, and throat infections Vomiting Nausea Nasal signs or symptoms Throat and tonsil discomfort or pain Burning or stinging sensation Dizziness
433
286(66)
of patients
and
NS Dose 20 mg 197
126(64)
190 (44)
73 (37)
24 (6) 24 (6) 21 (5)
13 (7) 7 (4) 5 (3)
19(4)
6 (3)
16 (4) 14 (3) 12 (3)
4 (2) 7 (4) 9 (5)
‘AEs were defined as any untoward medical events occurring after the use of study drug. tAlthough there were 437 patients in the tolerability population, not all patients treated the initial attack with the lo-mg dose, and not all doses were titrated up to the 20.mg dose.
were considered drug-related AEs: 1 patient had received a hepatitis B vaccination before laboratory testing and was discontinued from the study; the other patient experienced only mild elevations in ALT and AST and remained in the study. No patients experienced drug-related changes in vital signs or ECG findings from baseline to study exit. No clinically significant alterations in height outside the normal growth pattern were observed after 1 year of treatment in patients for whom there was complete information (1851187; 99% at ?lO% of baseline). EfSicacy For all doses combined, 75% of patients treated ~1 attack per month, 19% treated between 1 and 2 attacks per month, and 7% treated 22 attacks per month. This resulted in a mean of 0.78 attacks treated
per patient per month (range, 0.074.58; SD, 11.49). For all treated attacks, the overall percentage of patients reporting headache response 2 hours after dosing was similar between the IO- and 20-mg groups (Figure 2). Headache response during the first 6 months of treatment with sumatriptan 10 and 20 mg was similar to the overall (l-year) response, and headache response increased slightly during the second 6month period. Figure 3 presents the headache response 2 hours after dosing by number of attacks in which 210 patients treated a moderate or severe attack. For all treated attacks, the overall percentage of patients with a pain-free response 2 hours after dosing was similar between treatment groups (Figure 2). The pain-free response in attacks treated with sumatriptan NS 10 and 20 mg during the first 6 months was similar to the overall
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CLINICALTHERAPEUTICS'
n
Sumatriptan NS 10 m9 n Sumatriptan NS 20 mg
VJ 70 ;
60
52
$f 50 5 8
40 30
OW?d
Second 6 ’ Months
First 6 Months
Overall
Headache Response 2 Hours After Dosing
Second 6 Months
First 6 Months
Pain-Free Response 2 Hours After Dosing
Figure 2. Incidence of headache response and pain-free response 2 hours after dosing with sumatriptan nasal spray (NS) 10 and 20 mg in all treated attacks, by 6month period and overall (12 months). Headache response was defined as a reduction in predose headache pain severity from moderate or severe to mild or no pain. Pain-free response was defined as a reduction from moderate or severe predose pain to no pain.
-D- Sumatriptan + Sumatriptan
NS 10 m9 NS 20 mg
100 90 80 CA70 5
60
2
50
1
3
5
7
9
11
13
15
17
19
21
23
No. of Attacks Figure 3. Headache response 2 hours after dosin g. by number of attacks, with sumatriptan nasal spray (NS) 10 and 20 mg for attacks in which z IO adolescents treated moderate or severe migraine pain.
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A.D. ROTHNER ET AL.
Table IV. Incidence of headache recurrence, by attack (all doses), and mean time to recurrence during the first and second 6-month periods.“’ Sumatriutan NS Dose
No. (%) of attacks with headache recurrence Overall First 6 months Second 6 months Mean time to headache recurrence, h Overall First 6 months Second 6 months
10mg
20 mg
181/1480 (12) 151/1055 (14) 301425 (7)
1331905 (15) 641’435 (15) 69/470 (15)
8.2 8.4 7.1
10.4 10.2 10.6
NS = nasal spray. *Headache recurrence was defined as a significant worsening of pain (from no or mild pain to moderate or severe pain) in patients who had reported headache response 2 to 24 hours after dosing.
pain-free response. Pain-free response increased in the lo-mg group during the second 6-month period.
Headache Recurrence Rescue Medication
and Use of
Overall, the incidence of headache recurrence was low in both treatment groups (Table IV), although patients who received sumatriptan NS 10 mg had a shorter time to recurrence than those receiving the 20mg dose. Recurrence rates and mean time to recurrence in the lo-mg treatment group were lower in the second 6-month period than in the first 6-month period. Headache recurrence and time to recurrence were generally similar over time in the 20-mg group. Overall, rescue medication or a second dose of sumatriptan was used in 24% of all attacks in the IO-mg group and 32% in the 20-mg group. Rescue medication use was similar in the 2 treatment groups over the two 6-month periods; however, the lo-
mg group used less rescue medication during the second 6-month period (16%) than in the first 6-month period (27%). When patients used a second dose of sumatriptan NS 10 or 20 mg, the incidence of AEs was decreased compared with that in patients who used 1 dose (48% and 43% vs 63% and 60%, respectively).
Dose Adjustment The sumatriptan dose was decreased in 2.3% (10/437) of all patients (5 patients from 10 to 5 mg, 5 patients from 20 to 10 mg) to optimize tolerability. The dosage was increased in 50% (220/437) of all patients (218 patients from 10 to 20 mg, 2 patients from 5 to 10 mg) to optimize efficacy.
DISCUSSION This large-scale assessment of the l-year tolerability and efficacy of sumatriptan NS 10 and 20 mg for the treatment of acute migraine in adolescents was conducted in
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a manner that mimicked real-life unrestricted medication use. All doses of sumatriptan NS exhibited a low incidence of drug-related AEs that did not increase over time or multiple attacks. Taste disturbance was the most commonly reported drugrelated ,4E. Most AEs were mild or moderate in intensity, with only I drug-related serious AE reported in >3200 treated attacks. It is significant that use of a second dose of sumatriptan NS was not associated with an increase in AEs, and few investigators lowered the dosage of sumatriptan to optimize tolerability. Less than 5% of patients withdrew due to drug-related AEs. and when taste disturbance was eliminated from the tabulations, this rate declined to <2% of all patients, indicating a high tolerability in these adolescents. The incidence of AEs per patient ovel 1 year was higher than that reported in the earlier single-attack, placebo-controlled study in adolescents (single-attack. overall: 10 mg, 49%; 20 mg, 55%; placebo, 40%).13 However. the incidence of drugrelated AEs in our study was similar to that reported by the earlier investigators and may more accurately reflect the multiple-attack response to sumatriptan in this population (single-attack, drugrelated: IO mg, 38%; 20 mg, 40%: placebo, 18%). When AEs related to taste disturbance were excluded, the long-term tolerability in adolescents per attack was comparable to that reported for placebo in the single-attack study (single-attack, drug-related. without taste disturbance: placebo. 39%). It is important that no dose-related differences in AEs were identified. In general, the incidence of AEs decreased in patients who treated attacks more frequently, perhaps because they became familiar with the treatment over time or because those with fewer overall AEs stayed
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in the study longer. Furthermore. the number of attacks with drug-related AEs without taste disturbance was similar to that reported for adults in a multiple-attack study,‘O as well as that in a 12-month tolerability study.‘” The diagnosis of the I drug-related serious AE was unclear. Although originally reported as a facialnerve ischemic event, this AE may have been related to concurrent sphenoid sinusitis. No unusual risk or treatment factor was identified that could explain the occurrence of this event in a patient who had had several previous uneventful exposures to sumatriptan. This study also assessed the 1-year effcacy of sumatriptan NS in adolescents. The NS formulation demonstrated consistently high rates of headache response (>70%) and pain-free response (~~40%) over multiple attacks, with no evidence that long-term USCaffected the frequency of attacks. Overall. 2-hour efficacy rates exceeded those in the single-attack study (IO mg, 64%: 20 mp. 630/c).13 with the highest efficacy rates reported in the second 6 months of the study. perhaps as a function of sample enrichment with sumatriptan responders over time. Alternatively. patients who stayed in the study longer may have learned the most effective treatment method and were able to maximize the therapeutic benefit of sumatriptan NS. Interestingly, the incidence of headache recurrence was lower over this l-year period than in the single-attack study (I 0 mg, 20%; 20 mg, 16%)’ ‘: it paralleled the higher efficacy patterns. which, coupled with the lower use of rescue medication. indicated a strong pattern of effectiveness in adolescents. Efficacy results 2 hours after dosing were similar to-if not higher than-those reported by adults in earlier sumatriptan NS studies ( 10 mg: 46s.”
A.D. ROTHNER ET AL.
54%,‘O 43%-54%t6; 20 mg: 64%: 60%,t” 62%-63%t6). These results enhance our understanding of sumatriptan’s effectiveness across age groups. The fact that patient numbers declined over the extended study period may be a limitation of the study. Patients who experienced undesirable AEs or who were nonresponders to sumatriptan may have withdrawn as the study progressed, potentially enriching the second 6 months of the study with sumatriptan responders. Although the study’s l-year length may have contributed to the attrition of patient numbers, it also provided data not previously available to clinicians regarding the tolerability of sumatriptan NS and the consistency of response in adolescents over multiple attacks. The open-label, unrestricted-use design simulated real-life experience with migraine treatment in this patient population. Without a placebo group, however, the observed results cannot be attributed exclusively to sumatriptan NS.
CONCLUSIONS Sumatriptan NS 10 and 20 mg were well tolerated by adolescents over multiple attacks, with an incidence of AEs similar to that reported in a previous placebocontrolled, single-attack study in adolescents. l3 No dose-related differences were observed, and a second dose of sumatriptan did not increase the incidence of AEs. The most commonly reported AE was taste disturbance. Few patients required dose adjustments to optimize tolerability, and the dose was increased in 50% of patients to optimize efficacy. Rates of headache response and pain-free response were consistently high over 1 year of treatment. Headache recurrence and use of rescue medication were low.
ACKNOWLEDGMENTS The authors acknowledge the writing and editorial assistance of Barbara Wilson in preparing this manuscript. The other clinical investigators who participated in this study were as follows: James Adelman, Greensboro, North Carolina; Peter Ahmann, Marshfield, Wisconsin; Richard K. Bath, Cincinnati, Ohio; Joan Benz, Cedar Rapids, Iowa; Gary Berman, Minneapolis, Minnesota; David Bettis, Boise, Idaho; Mark Blatter, Pittsburgh, Pennsylvania; Jeffrey Blumer, Cleveland, Ohio; Paul Brownstone, Boulder, Colorado; Roger Cady, Springfield, Missouri; Richard Colan, Milwaukee, Wisconsin; Michael Edmond, Austin, Texas; Keith Edwards, Bennington, Vermont; Victor Elinoff, Endwell, New York; Arthur H. Elkind, Mt. Vernon, New York: Thomas Enlow, Akron, Ohio; Michael Greenberg, Waldorf, Maryland; Michael Haugh, Tulsa, Oklahoma; James Hedrick, Bardstown, Kentucky; Raymond Kandt, High Point, North Carolina; Robert Kaniecki, Pittsburgh, Pennsylvania; Jack Klapper, Denver, Colorado; Hubert Leonard, Portland, Oregon; Donald Lewis, Norfolk, Virginia; Steve Linder, Dallas, Texas; Joseph Maytal, New Hyde Park, New York; Robert Nahouraii, Charlotte, North Carolina; William Patterson, Birmingham, Alabama; Arthur Prensky, St. Louis, Missouri; Anthony Puopolo, Milford, Massachusetts; Phillip S. Riback, Albany, New York; Joel Rutman, San Antonio, Texas; Joel Saper, Ann Arbor, Michigan; Lawrence Seiden, Catonsville, Maryland; Fred Sheftell, Stamford, Connecticut; Susan Smietana, Detroit, Michigan; Egilius Spierings, Wellesley Hills, Massachusetts; Richard Taylor, Towson, Maryland; Russell Walker, Phoenix, Arizona; Thomas Ward. Lebanon,
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New Warren Wasiewski, Lancaster, Pennsylvania; Terry Watkin, Fairfax, Virginia; and Jeanette Wendt, Tucson, Arizona. (Protocol #SUMA3006) Address correspondence to: A. David Rothner, MD, The Cleveland Clinic. Desk S7 1, 9500 Euclid Avenue, Cleveland, OH 44195 (e-mail: [email protected]). REFERENCES I. Mortimer MJ, Kay J, Jaron A. Childhood migraine in general practice: Clinical features and characteristics. C~p/7cll~l/,qia. 1992: 12:238-243. 2. McGrath P. Larsson B. Headache in children and adolescents. Plrirl MLUZChild. I997:6:844-86 I. 3. Winner P, Martinez W, Mate L, Belle L. Classification of pediatric migraine: Proposed revisions to the IHS criteria. Hcmltrc~hr. I YV5;35:407-4 10. 4. Winner P, Putnam G, Suiers J, et al. Demographic and migraine characteristics of adolescent patients: The Glaxo Wellcome Adolescent Clinical Trials Database. Presented at: American Headache Society Annual Scientific Meeting: June 22-26, 2000: Montreal, Quebec, Canada. 5. When it comes to migraine, children are not small adults. Dr1cg.s Tiler Prrspc~c‘t. 1999;14:1 l-14. 6. Hamalainen M. Migraine Guidelines for treatment. 1’)98;10:105-I 17.
9. Pcikert A, Becker WJ, Ashford EA, et al.
Sumatriptan nax~l spray: A dose-ranging study in the acute treatment of migraine. El//. J Ncwml. I Y99;6:43-39. IO. Diamond S, Elkind A, Jackson RT. et al. Multiple-attack efficacy and tolerability of sumatriptan nasal spray in the treatment of migraine. Ad7 /+rm Mctl. 1998: 7:234-240. 1 I. Dahlof CG, Boes-Hansen S, Cederberg CG, et al. How does sumatriptan nasal spray perform in clinical practice? Cq/w I&&. I998;18:278-2x2. 12, Christensen M. Mootern R, Jabbour J, Fuwau E. Pharmacokinetics (PK) of sumatriptan nasal spray in aclolescent mgraineur$. CIiil Phol-nzilwi T/ICI: 2000: 67: 103.
13. Winner P, Rothner AD, Saper J. et al. Sumatriptan na\al spray for treatment of adolescent migraine. Pdinfrics. 2000: 106: 9X9-997. 14. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephtrlalgicl. I YXX;X(Suppl 7): l-96. 1.5. Reches A. The long-term tolerability, safety, and efficacy of sumatriptan 20 mp nasal spray in the acute treatment of mi-
in children:
praine. Presented at: 7th International Headache Congress; September 16-20.
CNS DIX~S.
1995; Toronto. Ontario. Canada.
7. Farkas V. Appropriate migraine therapy for children and adolescents. Cqd~nlalgicr. 1999; lV(Suppl 23):24-28.
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8. Rothner AD. The migraine syndrome in children and adolescents. Pczcfiurr-Ntwrol. 1986;2:121-126.
16. Ryan R, Elkind A. Baker CC. et al. Sumatriptan nasal spray for the acute treatment of migraine. Results of two clinical studies. Neurology. 1997~49: 1225-I 230.
THERAPEUTICSVVOL.
22, NO. 12,200O
One-Year Tolerability and Efficacy of Sumatriptan Spray in Adolescents with Migraine: Results of a Multicenter, Open-Label Study
Nasal
A. David Rothner, MD,’ Paul Winner, DO,2 Robert Nett, MD,3 Mahnaz Asgharneja f, PharmD,4 Antonio Luurenza, MD,4 Randall Austin, MA, and Margaret Peykamiun4 ‘The Cleveland Clinic, Cleveland, Ohio, 2Pafm Beach Headache Centel; West Palm Beach, Florida, 3San Antonio Center for Clinical Research, San Antonio, Texas, and 4Glaxo Wellcome Inc, Research Triangle Park, North Carolina
ABSTRACT Objective: The objective of this study was to determine the l-year tolerability and efficacy of sumatriptan nasal spray (NS) at doses of 5, 10, and 20 mg for the treatment of acute migraine in adolescents. Methods: This was a prospective, multicenter, open-label, 1-year, multiple-attack study. Adolescents (aged 12-17 years) with a >6-month history of migraine with or without aura, 2 to 8 moderate or severe migraines per month, and a typical migraine duration of ~4 hours were eligible for participation. After initial treatment with sumatriptan 10 mg, the dose could be adjusted down to 5 mg or up to 20 mg at the investigator’s discretion to optimize tolerability or efficacy. Patients could treat an unlimited number of moderate or severe migraine attacks, provided there was a 24-hour headache-free period between treated attacks and a 2-hour period between doses of sumatriptan NS. A second dose of sumatriptan NS was available for headache recurrence 2 to 24 hours after initial treatment; no more than 2 doses could be used within a 24-hour period. Adverse events, vital signs, electrocardiographic and physical findings, and laboratory variables were assessed. Headache response (reduction of moderate/severe predose pain to mild/no pain) and painfree response (reduction of moderate/severe predose pain to no pain) were reported by patients 2 hours after dosing. Portions of this study were presented at the American 2000, Montreal, Quebec, Canada. Accepted for publication
November
Printed in the USA. Reproduction
0149.2918/00/$19.00
Headache
Society Annual Scientific Meeting, June 22-26,
7, 2000. in whole or part is not permitted.
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CLINICAL
Results: A total of 437 patients treated 21 migraine; 3272 total attacks were treated, with 3675 drug exposures (mean. 1.1 dose/attack). Patients had a mean age of 14.1 years, 91% were white, and 53% were female. Seven patients used the 5-m:: dose; meaningful conclusions concerning this dose could not be made. Drug-related adverse events were reported in 33% of attacks with the IO-mg dose and 31% with the 20-mg dose; most were related to taste disturbance. Adverse events did not increase with a second dose or over time. Four percent (16/437) of patients withdrew due to drug-related adverse events. One serious adverse event, a facial-nerve ischemic event (IO-mg dose), was considered drug related. No drugrelated changes in vital signs or electrocardiographic findings were observed. Headache response 2 hours after dosing was reported by 76% of patients taking the IO-mg dose and 72% of those taking the 20-mg dose. Pain-free response 2 hours after dosing was reported by 43% and 40% of patients in the IO- and 20-mg groups, respectively. Cordusions: Based on these results, sumatriptan NS at doses of 10 and 20 mg was well tolerated and effective in the l-year treatment of multiple migraine attacks in adolescents. Key words: migraine, adolescent, sumatriptan, tolerability, multiple attacks. (Cl&r Thet: 2000;22: 1533-I 546)
INTRODUCTION Migraine is a common, episodic neurologic disorder with a worldwide prevalence of 8% to 20% in adults and 4% to 10% in adolescents.’ The onset of migraine often occurs in childhood. and many patients experience their first episode by the end of
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THERAPEUTICS
adolescence.’ Migraine occurs in equal proportions of males and females before puberty but occurs predominantly in females (3:l) after menarche.’ The clinical presentation of migraine in adolescents is similar to that in adults; however, adolescents experience a higher incidence of associated symptoms and pulsating bilateral pain. and a shorter duration of attacks compared with adults.3.” In general. migraine therapy in adolescents has focused on avoidance of trigger factors. adequate sleep, and limited treatment with nonsteroidal anti-inllammatory medications.5-x Sumatriptan nasal spray (NS) has been proved effective in adults who experience a rapid onset of migraine pain and associated symptoms.” -I ’ Results of a recent study of sumatriptan NS 20 mg” indicated that its pharmacokinetic parameters are similar in adolescents and adults. and suggested that dosing used in adolescents should be similar to that used in adults. In addition, a single-attack. placebo-controlled study in adolescents’? indicated that sumatriptan NS was effective and well tolerated. with the 20-mg dose having the best overall efficacy and tolerability. In that study, headache response was greater with sumatriptan NS 10 and 20 mg compared with placebo as early as 1 hour after dosing (56% and 56% vs 41 c/c. respectively: P < 0.05). Furthermore, pain-free response 2 hours after dosing was greater with sumatriptan NS 20 mg compared with placebo (36% vs 25%, respectively: P < O.OS), and photophobia and phonophobia were significantly reduced compared with placebo (36% vs 48% and 23% vs 44%. respectively: P < 0.05). Taste disturbance was the most commonly reported adverse event (AE), and no drug-related serious AEs or clinically relevant changes in lab-
A.D. ROTHNER
ET AL.
oratory variables, electrocardiographic findings, or vital signs were reported. Currently, no formulation of sumatriptan has been approved for use in adolescents. Although the results of the single-attack, placebo-controlled study I3 are encouraging, further investigation into the long-term tolerability of sumatriptan NS over multiple attacks is needed in this population. We report the results of a large-scale, multipleattack, open-label study of the unrestricted use of sumatriptan NS 5, 10, and 20 mg to assess its long-term (1 year) tolerability and efficacy in the treatment of acute migraine in adolescents.
Females were excluded if they were pregnant or breast-feeding, or were sexually active without using adequate contraception. Patients could not use ergotaminecontaining drugs or derivatives or any other 5-HT,-agonist within 24 hours before or after treatment with study medication. Monoamine oxidase inhibitors could not be used for ~2 weeks before screening and throughout the course of the study. Selective serotonin reuptake inhibitors could not be used from screening through study exit. With the exception of these 2 types of agents, patients were allowed to continue prophylactic migraine medication.
PATIENTS AND METHODS
Study Procedures
Inclusion and Exclusion
Criteria
Males and females, aged 12 to 17 years, with a diagnosis of migraine with or without aura based on International Headache Society criteria (categories 1.1 and 1.2)t4 and having a 26-month history of moderate or severe attacks were eligible for study participation. Patients were required to have a history of 2 to 8 moderate or severe migraine attacks per month for each of the 2 months preceding study enrollment and a typical migraine duration of ~4 hours. Patients were also required to have ~15 days of tension headache per month and to have failed to achieve relief with 21 over-the-counter or prescription migraine medication. Patients were excluded from the study if they had a history of congenital heart disease, cardiovascular disease, Prinzmetal’s angina, atherosclerotic disease or cerebrovascular pathologic conditions including stroke, any other clinically significant medical condition, or evidence of alcohol, drug, or substance abuse within the previous year.
Forty-six sites in the United States received institutional review board approval to enroll patients. Patients and their parents or legal guardians provided written informed consent before study enrollment. Patients were screened in a migrainefree state. At screening, demographic information and medical and migraine histories were obtained, and complete physical and neurologic examinations were conducted, including vital signs, clinical laboratory testing (hematology, blood chemistry, and urinalysis), serum pregnancy testing (females), and 12-lead electrocardiography (ECG). Patients who met the inclusion criteria received instruction in the study procedures and use of the NS device and patient diary. Patients could treat an unlimited number of moderate or severe migraine attacks with sumatriptan NS, provided a 24hour headache-free period was maintained between treated attacks and a 2-hour period was maintained between doses. A second dose of sumatriptan NS was available for the treatment of headache recur-
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CLINICAL
rence 2 to 24 hours after initial treatment; no more than 2 doses of sumatriptan NS could be used within any 24-hour period (maximum, 40 mg). After initial treatment with sumatriptan 10 mg, dosage adjustment down to 5 mg or up to 20 mg could be made at the investigator’s discretion to optimize tolerability or efficacy. No patient was allowed to use >l dose level of sumatriptan NS at a single time. Patients were required to treat their migraines at home in the presence of a parent or guardian and to record the date, time, and pain intensity of each attack, as well as the time study drug was taken. Patients were instructed to contact study personnel by telephone after treatment of the first migraine. Patients returned to the clinic at 3-month intervals and at study exit (I year after enrollment); at these visits, physical and neurologic examinations and assessment of vital signs were conducted, medical and migraine histories were updated, and pregnancy tests were performed. An independent cardiologist with experience in adolescent cardiology assessed baseline, exit, or unscheduled ECGs when this was clinically indicated or required by the protocol. Study personnel contacted patients approximately every 6 weeks to determine compliance with enrollment criteria, particularly with respect to pregnancy, use of concomitant medications, and dosing procedures. Patients who had not treated a migraine within 3 months were asked to return to the clinic for retraining and reevaluation of eligibility.
End Points The primary study end point was the occurrence and severity of AEs at each dose of sumatriptan NS. Secondary end
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THERAPEUTICS”
points included headache response and pain-free response 2 hours after dosing, headache recurrence, use of rescue medication, proportion of patients whose sumatriptan dose was adjusted, and nunIber of NS devices used per attack at each dose.
Tolerability Assessment Tolerability assessments included the incidence and severity ofAEs (mild, moderate, or severe), as well as the occurrence of abnormalities in physical findings, vital signs. clinical laboratory test results, and ECGs. An AE was defined as any untoward medical event occurring after the use of study drug. A serious AE was defined as any medical occurrence that was fatal, life-threatening, or disabling: that required hospitalization; or that caused congenital anomaly in a patient’s offspring. Cancer and overdose of study drug were also considered serious AEs. Study personnel queried patients concerning AEs after treatment of the first migraine, at each study visit, and during routine follow-up telephone calls. Severity ofAEs was assigned by investigators based on their professional judgment.
Efficacy Assessment Patients rated their headache pain before and 2 hours after dosing using a 4-point pain scale (0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain). Headache response was defined as a reduction in predose headache pain severity from moderate or severe to mild or no pain (pain score of 2 or 3 reduced to I or 0). Pain-free response was defined as a reduction from moderate or severe predose pain to no pain (pain score of 2 or 3 reduced to 0).
A.D. ROTHNER
ET AL.
Assessment of Headache Recurrence and Use of Rescue Medication Headache recurrence was defined as a significant worsening of pain (from no or mild pain to moderate or severe pain) 2 to 24 hours after the first dose of sumatriptan in those patients who had reported headache response 2 hours after dosing. Use of rescue medication was defined as use of any medication to treat migraine pain or associated symptoms 2 to 24 hours after taking study drug. Use of a second dose of study drug or rescue medication was recorded in the patient diary. Statistical Analysis All statistical analyses were performed using SAS@ software (SAS Institute, Inc, Cat-y, North Carolina). It was determined that -400 patients were necessary to ensure 300 assessable patients with 26 months of treatment data and 100 patients with 1 year of treatment data. All patients who treated 21 attack with study medication were included in the tolerability population. The intent-to-treat (ITT) population was composed of patients who treated an attack with study medication and returned assessable efficacy data. Last observations were carried forward to account for missing assessments of headache severity. If rescue medication or a second dose of sumatriptan was taken between dosing and the 2-hour assessment, a pain intensity of “severe” was assigned to the 2-hour assessment. Because of the openlabel nonrandomized study design that allowed investigators to adjust the dose based on individual patients’ needs, inferences drawn from statistical comparisons of tolerability and efficacy between treatment groups would not have been valid.
Therefore, descriptive statistics are reported. A per-protocol analysis was not performed. The tolerability analyses included extentof-exposure and AE profiles. Extent of exposure included the total number of treated attacks, the actual number of doses taken, and the mean number of doses per patient and per attack. AEs were translated into preferred terms, then sorted into group terms. The overall frequency of patients reporting AEs was tabulated for each dose of sumatriptan. Separate tabulations were made by numbers of patients for drug-related AEs, event intensity, and serious AEs. Abnormalities in clinical laboratory test results, vital signs, ECG data, and physical findings were summarized over the l-year study. The efftcacy analyses summarized headache and demographic characteristics, headache response, pain-free response, and headache recurrence at baseline and 2 hours after dosing by dose and number of attacks using descriptive statistics (frequency counts, percentages, means, SDS, and ranges, as applicable). Values were generated for the l-year (overall) and 6month time points. The mean number of NS devices used per attack was calculated for each sumatriptan dose.
RESULTS Patients Of the 518 patients enrolled in the study, 437 patients treated 21 migraine with sumatriptan NS (tolerability population). Twelve patients in the tolerability population did not return efficacy data; therefore, the ITT population included 425 patients. One hundred eighty-nine (36%) patients completed all 12 months of the
1537
CLINICAL THERAPEIJTICS”’
study.
most common reasons
presented.
( 152/206; 74%) than were females (I 14/23 I; 49%). Although 60% (260/433) of all patients for whom there was complete information had no prior 5-HT,-agonist exposure, 407~ (I 73/433) had used a sumatriptan formulation before study entry. At baseline, 46% of attacks in the IOmg group and 53% in the 20-mg group were severe in intensity. More than 75% of all patients treated headache pain within 2 hours of its onset (IO-mg group, 75%; 20-mg group, 78%), and mean times to treatment were identical ( I .S hours). Tolerability A total of 3272 attacks were treated in the tolerability population; 3222 attacks were treated in the ITT population. There were a total of 3675 drug exposures: 2374 in the first 6 months of the study and 130 1 in the second 6 months. Overall, the mean
1538
number of doses used per patient was 8.4 (range, l-54 doses). A mean of 1.1 NS devices was used per attack; this number did not vary by dose. A summary of the overall incidence of AEs by number of patients is presented in Table I. In general. the incidence of AEs was similar between treatment groups. Younger patients reported a higher rate of overall AEs than older patients. However. when taste disturbance was excluded. the incidence of AEs in older and younger patients was similar. AE rates were also similar in males and females receiving sumatriptan 20 mg, although males reported fewer AEs than females in the IOmg group. No differences were observed in the rate of AEs by body weight or dose. The incidence of overall AEs was lowe] in patients in the IO- and 20-mg groups who treated >2 attacks per month compared with those who treated
A.D. ROTHNER ET AL.
Table I. Incidence of overall and drug-related patients and demographic factors.
adverse
events
(AEs),* by number
of
Sumatriptan NS Dose 20 mg
IOmg Total no. of patients’ No. (%) with AEs No. (%) with drug-related AEs Demographic distribution of patients with AEs, no. (%) Age, Y 12-14 15-17 Sex Female Male Body
weight,
433 286 (66) 226 (52)
182/262
(69)
104/171
(61)
164/229
(72)
122/204
(60)
197 126 (64) 88 (45)
83/l 18 (70) 43/79
(54)
66/102 (65) 60/95 (63)
kg
<50 250
93/ 134 (69) 192/298;
(64)
34155 (62) 921142
(65)
NS = nasal spray. ‘AEs were defined as any untoward medical events occurring after the use of study drug. +Although there were 437 patients in the tolerability population, not all patients treated the initial attack with the IO-mg dose, and not all doses were titrated up to the 20-mg dose. *Data were missing for 1 patient.
was similar for the IO-mg (45%) and 20mg (48%) groups per patient, per attack (15%, both 10 and 20 mg), and by age group (48% and 49% in younger patients vs 42% and 47% in older patients, respectively). The percentage of drug-related AEs per patient was slightly higher with the lo-mg dose (52%) than the 20-mg dose (45%) (Table I). Per attack, drug-related AEs occurred in 33% (10 mg) and 31% (20 mg) of all attacks. In the analysis by attack, taste disturbance was also the most commonly reported drug-related AE in the IO-mg (29%) and 20-mg (26%) groups. When taste disturbance was excluded from the tabulations, the incidence of drug-related AEs by attack declined to 7% with both 10 and 20 mg.
Only 1 drug-related serious AE was reported, a facial-nerve ischemic event, which occurred after treatment with sumatriptan 10 mg. The patient was withdrawn from the study; 10 months after the event, the symptoms had resolved, with mild, intermittent sequelae. Few patients (22/437; 5%) discontinued study participation due to AEs; 16 (4%) of these withdrawals were considered drug related: taste disturbance (8 patients), neurologic changes (left hand numbness, 1 patient; facial numbness, 1 patient), migraine and associated symptoms (3 patients), chest pain (2 patients), and abnormal laboratory values ( 1 patient). Two patients had asymptomatic changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values that
1539
CLINICAL THERAPEUTICS
’
Table II. Incidence of overall and drug-related adverse events (AEs), by number of patients (all doses) and number of attacks (all attacks), during the first and second 6-month periods. Sumatriptan NS Dose
AEs by no. (‘5) of patients First 6 months, total patient\ Overall Drug-related Second 6 months, total patients O\ierall Drug-related AEs by no. (%) of attacks First 6 months, total attacks Overall Drug-related Second 6 months, total attacks Overall Drug-related
429 274 (64) 218 (51) I18 64 (54) 44 (37)
IS0 95 (63) 65 (43) 133 73 (551 51 (3X)
147X 620 (42) 542 (37) so0 13s (29) Il.7 (23)
616 240 (39) 190 (31) 654 237 (35) 201 (31)
NS = nasal spray. ‘An AE was defined as any untoward
medical went
occurring
after the use of study drur.
AEs wth taste disturbance BJDrug-related AEs with taste disturbance q Overall AEs without taste disturbance Cl Drug-related AEs without taste disturbance 1 Overall
100 90 80
Sumatriptan NS Dose Figure 1. Incidence of overall adverse events (AEs), drug-related AEs, overall AEs without taste disturbance, and drug-related AEs without taste disturbance, by number of attacks and dose, in a l-year study of sumatriptan nasal spray (NS) in adolescents. An AE was defined as any untoward medical event occurring after the use of study drug.
1540
A.D. ROTHNER ET AL.
Table III. Adverse events (AEs) occurring at a rate of 23%, by number dose of sumatriptan nasal spray (NS).’ Sumatriptan IOmg Total no. of patients’ No. (%) with AEs Most commonly reported AEs, no. (%) Taste disturbance Ear, nose, and throat infections Vomiting Nausea Nasal signs or symptoms Throat and tonsil discomfort or pain Burning or stinging sensation Dizziness
433
286(66)
of patients
and
NS Dose 20 mg 197
126(64)
190 (44)
73 (37)
24 (6) 24 (6) 21 (5)
13 (7) 7 (4) 5 (3)
19(4)
6 (3)
16 (4) 14 (3) 12 (3)
4 (2) 7 (4) 9 (5)
‘AEs were defined as any untoward medical events occurring after the use of study drug. tAlthough there were 437 patients in the tolerability population, not all patients treated the initial attack with the lo-mg dose, and not all doses were titrated up to the 20.mg dose.
were considered drug-related AEs: 1 patient had received a hepatitis B vaccination before laboratory testing and was discontinued from the study; the other patient experienced only mild elevations in ALT and AST and remained in the study. No patients experienced drug-related changes in vital signs or ECG findings from baseline to study exit. No clinically significant alterations in height outside the normal growth pattern were observed after 1 year of treatment in patients for whom there was complete information (1851187; 99% at ?lO% of baseline). EfSicacy For all doses combined, 75% of patients treated ~1 attack per month, 19% treated between 1 and 2 attacks per month, and 7% treated 22 attacks per month. This resulted in a mean of 0.78 attacks treated
per patient per month (range, 0.074.58; SD, 11.49). For all treated attacks, the overall percentage of patients reporting headache response 2 hours after dosing was similar between the IO- and 20-mg groups (Figure 2). Headache response during the first 6 months of treatment with sumatriptan 10 and 20 mg was similar to the overall (l-year) response, and headache response increased slightly during the second 6month period. Figure 3 presents the headache response 2 hours after dosing by number of attacks in which 210 patients treated a moderate or severe attack. For all treated attacks, the overall percentage of patients with a pain-free response 2 hours after dosing was similar between treatment groups (Figure 2). The pain-free response in attacks treated with sumatriptan NS 10 and 20 mg during the first 6 months was similar to the overall
1541
CLINICALTHERAPEUTICS'
n
Sumatriptan NS 10 m9 n Sumatriptan NS 20 mg
VJ 70 ;
60
52
$f 50 5 8
40 30
OW?d
Second 6 ’ Months
First 6 Months
Overall
Headache Response 2 Hours After Dosing
Second 6 Months
First 6 Months
Pain-Free Response 2 Hours After Dosing
Figure 2. Incidence of headache response and pain-free response 2 hours after dosing with sumatriptan nasal spray (NS) 10 and 20 mg in all treated attacks, by 6month period and overall (12 months). Headache response was defined as a reduction in predose headache pain severity from moderate or severe to mild or no pain. Pain-free response was defined as a reduction from moderate or severe predose pain to no pain.
-D- Sumatriptan + Sumatriptan
NS 10 m9 NS 20 mg
100 90 80 CA70 5
60
2
50
1
3
5
7
9
11
13
15
17
19
21
23
No. of Attacks Figure 3. Headache response 2 hours after dosin g. by number of attacks, with sumatriptan nasal spray (NS) 10 and 20 mg for attacks in which z IO adolescents treated moderate or severe migraine pain.
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A.D. ROTHNER ET AL.
Table IV. Incidence of headache recurrence, by attack (all doses), and mean time to recurrence during the first and second 6-month periods.“’ Sumatriutan NS Dose
No. (%) of attacks with headache recurrence Overall First 6 months Second 6 months Mean time to headache recurrence, h Overall First 6 months Second 6 months
10mg
20 mg
181/1480 (12) 151/1055 (14) 301425 (7)
1331905 (15) 641’435 (15) 69/470 (15)
8.2 8.4 7.1
10.4 10.2 10.6
NS = nasal spray. *Headache recurrence was defined as a significant worsening of pain (from no or mild pain to moderate or severe pain) in patients who had reported headache response 2 to 24 hours after dosing.
pain-free response. Pain-free response increased in the lo-mg group during the second 6-month period.
Headache Recurrence Rescue Medication
and Use of
Overall, the incidence of headache recurrence was low in both treatment groups (Table IV), although patients who received sumatriptan NS 10 mg had a shorter time to recurrence than those receiving the 20mg dose. Recurrence rates and mean time to recurrence in the lo-mg treatment group were lower in the second 6-month period than in the first 6-month period. Headache recurrence and time to recurrence were generally similar over time in the 20-mg group. Overall, rescue medication or a second dose of sumatriptan was used in 24% of all attacks in the IO-mg group and 32% in the 20-mg group. Rescue medication use was similar in the 2 treatment groups over the two 6-month periods; however, the lo-
mg group used less rescue medication during the second 6-month period (16%) than in the first 6-month period (27%). When patients used a second dose of sumatriptan NS 10 or 20 mg, the incidence of AEs was decreased compared with that in patients who used 1 dose (48% and 43% vs 63% and 60%, respectively).
Dose Adjustment The sumatriptan dose was decreased in 2.3% (10/437) of all patients (5 patients from 10 to 5 mg, 5 patients from 20 to 10 mg) to optimize tolerability. The dosage was increased in 50% (220/437) of all patients (218 patients from 10 to 20 mg, 2 patients from 5 to 10 mg) to optimize efficacy.
DISCUSSION This large-scale assessment of the l-year tolerability and efficacy of sumatriptan NS 10 and 20 mg for the treatment of acute migraine in adolescents was conducted in
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CLINICAL
a manner that mimicked real-life unrestricted medication use. All doses of sumatriptan NS exhibited a low incidence of drug-related AEs that did not increase over time or multiple attacks. Taste disturbance was the most commonly reported drugrelated ,4E. Most AEs were mild or moderate in intensity, with only I drug-related serious AE reported in >3200 treated attacks. It is significant that use of a second dose of sumatriptan NS was not associated with an increase in AEs, and few investigators lowered the dosage of sumatriptan to optimize tolerability. Less than 5% of patients withdrew due to drug-related AEs. and when taste disturbance was eliminated from the tabulations, this rate declined to <2% of all patients, indicating a high tolerability in these adolescents. The incidence of AEs per patient ovel 1 year was higher than that reported in the earlier single-attack, placebo-controlled study in adolescents (single-attack. overall: 10 mg, 49%; 20 mg, 55%; placebo, 40%).13 However. the incidence of drugrelated AEs in our study was similar to that reported by the earlier investigators and may more accurately reflect the multiple-attack response to sumatriptan in this population (single-attack, drugrelated: IO mg, 38%; 20 mg, 40%: placebo, 18%). When AEs related to taste disturbance were excluded, the long-term tolerability in adolescents per attack was comparable to that reported for placebo in the single-attack study (single-attack, drug-related. without taste disturbance: placebo. 39%). It is important that no dose-related differences in AEs were identified. In general, the incidence of AEs decreased in patients who treated attacks more frequently, perhaps because they became familiar with the treatment over time or because those with fewer overall AEs stayed
1544
THERAPEUTICS
in the study longer. Furthermore. the number of attacks with drug-related AEs without taste disturbance was similar to that reported for adults in a multiple-attack study,‘O as well as that in a 12-month tolerability study.‘” The diagnosis of the I drug-related serious AE was unclear. Although originally reported as a facialnerve ischemic event, this AE may have been related to concurrent sphenoid sinusitis. No unusual risk or treatment factor was identified that could explain the occurrence of this event in a patient who had had several previous uneventful exposures to sumatriptan. This study also assessed the 1-year effcacy of sumatriptan NS in adolescents. The NS formulation demonstrated consistently high rates of headache response (>70%) and pain-free response (~~40%) over multiple attacks, with no evidence that long-term USCaffected the frequency of attacks. Overall. 2-hour efficacy rates exceeded those in the single-attack study (IO mg, 64%: 20 mp. 630/c).13 with the highest efficacy rates reported in the second 6 months of the study. perhaps as a function of sample enrichment with sumatriptan responders over time. Alternatively. patients who stayed in the study longer may have learned the most effective treatment method and were able to maximize the therapeutic benefit of sumatriptan NS. Interestingly, the incidence of headache recurrence was lower over this l-year period than in the single-attack study (I 0 mg, 20%; 20 mg, 16%)’ ‘: it paralleled the higher efficacy patterns. which, coupled with the lower use of rescue medication. indicated a strong pattern of effectiveness in adolescents. Efficacy results 2 hours after dosing were similar to-if not higher than-those reported by adults in earlier sumatriptan NS studies ( 10 mg: 46s.”
A.D. ROTHNER ET AL.
54%,‘O 43%-54%t6; 20 mg: 64%: 60%,t” 62%-63%t6). These results enhance our understanding of sumatriptan’s effectiveness across age groups. The fact that patient numbers declined over the extended study period may be a limitation of the study. Patients who experienced undesirable AEs or who were nonresponders to sumatriptan may have withdrawn as the study progressed, potentially enriching the second 6 months of the study with sumatriptan responders. Although the study’s l-year length may have contributed to the attrition of patient numbers, it also provided data not previously available to clinicians regarding the tolerability of sumatriptan NS and the consistency of response in adolescents over multiple attacks. The open-label, unrestricted-use design simulated real-life experience with migraine treatment in this patient population. Without a placebo group, however, the observed results cannot be attributed exclusively to sumatriptan NS.
CONCLUSIONS Sumatriptan NS 10 and 20 mg were well tolerated by adolescents over multiple attacks, with an incidence of AEs similar to that reported in a previous placebocontrolled, single-attack study in adolescents. l3 No dose-related differences were observed, and a second dose of sumatriptan did not increase the incidence of AEs. The most commonly reported AE was taste disturbance. Few patients required dose adjustments to optimize tolerability, and the dose was increased in 50% of patients to optimize efficacy. Rates of headache response and pain-free response were consistently high over 1 year of treatment. Headache recurrence and use of rescue medication were low.
ACKNOWLEDGMENTS The authors acknowledge the writing and editorial assistance of Barbara Wilson in preparing this manuscript. The other clinical investigators who participated in this study were as follows: James Adelman, Greensboro, North Carolina; Peter Ahmann, Marshfield, Wisconsin; Richard K. Bath, Cincinnati, Ohio; Joan Benz, Cedar Rapids, Iowa; Gary Berman, Minneapolis, Minnesota; David Bettis, Boise, Idaho; Mark Blatter, Pittsburgh, Pennsylvania; Jeffrey Blumer, Cleveland, Ohio; Paul Brownstone, Boulder, Colorado; Roger Cady, Springfield, Missouri; Richard Colan, Milwaukee, Wisconsin; Michael Edmond, Austin, Texas; Keith Edwards, Bennington, Vermont; Victor Elinoff, Endwell, New York; Arthur H. Elkind, Mt. Vernon, New York: Thomas Enlow, Akron, Ohio; Michael Greenberg, Waldorf, Maryland; Michael Haugh, Tulsa, Oklahoma; James Hedrick, Bardstown, Kentucky; Raymond Kandt, High Point, North Carolina; Robert Kaniecki, Pittsburgh, Pennsylvania; Jack Klapper, Denver, Colorado; Hubert Leonard, Portland, Oregon; Donald Lewis, Norfolk, Virginia; Steve Linder, Dallas, Texas; Joseph Maytal, New Hyde Park, New York; Robert Nahouraii, Charlotte, North Carolina; William Patterson, Birmingham, Alabama; Arthur Prensky, St. Louis, Missouri; Anthony Puopolo, Milford, Massachusetts; Phillip S. Riback, Albany, New York; Joel Rutman, San Antonio, Texas; Joel Saper, Ann Arbor, Michigan; Lawrence Seiden, Catonsville, Maryland; Fred Sheftell, Stamford, Connecticut; Susan Smietana, Detroit, Michigan; Egilius Spierings, Wellesley Hills, Massachusetts; Richard Taylor, Towson, Maryland; Russell Walker, Phoenix, Arizona; Thomas Ward. Lebanon,
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CLINICAL THERAPEUTICS“
New Warren Wasiewski, Lancaster, Pennsylvania; Terry Watkin, Fairfax, Virginia; and Jeanette Wendt, Tucson, Arizona. (Protocol #SUMA3006) Address correspondence to: A. David Rothner, MD, The Cleveland Clinic. Desk S7 1, 9500 Euclid Avenue, Cleveland, OH 44195 (e-mail: [email protected]). REFERENCES I. Mortimer MJ, Kay J, Jaron A. Childhood migraine in general practice: Clinical features and characteristics. C~p/7cll~l/,qia. 1992: 12:238-243. 2. McGrath P. Larsson B. Headache in children and adolescents. Plrirl MLUZChild. I997:6:844-86 I. 3. Winner P, Martinez W, Mate L, Belle L. Classification of pediatric migraine: Proposed revisions to the IHS criteria. Hcmltrc~hr. I YV5;35:407-4 10. 4. Winner P, Putnam G, Suiers J, et al. Demographic and migraine characteristics of adolescent patients: The Glaxo Wellcome Adolescent Clinical Trials Database. Presented at: American Headache Society Annual Scientific Meeting: June 22-26, 2000: Montreal, Quebec, Canada. 5. When it comes to migraine, children are not small adults. Dr1cg.s Tiler Prrspc~c‘t. 1999;14:1 l-14. 6. Hamalainen M. Migraine Guidelines for treatment. 1’)98;10:105-I 17.
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